Quinolones and Macrolides

Question 1

What are quinolones?

Answer 1

Quinolones are derivatives of nalidixic acid which is a 1,8-naphthyridine urinary antibacterial agent.

Question 2

What is the activity spectrum of quinolones?

Answer 2

They are active mainly against gram-negative aerobic bacteria (e.g. Pseudomonas aeruginosa, Escherichia coli, etc.)
Also cover some gram-positive pathogens as their spectrum expands.

Question 3

What are the uses of quinolones?

Answer 3

They are widely used in the treatment of infections of the:
- genitourinary tract,
- upper and lower respiratory tract,
- skin and soft tissue

Question 4

What is the mechanism of action of quinolones?

Answer 4

They act by inhibiting the enzyme topoisomerase II (DNA gyrase) leading to impaired transcription of DNA to RNA, thus preventing protein synthesis.

Question 5

Quinolones are bacteriostatic at high concentrations.

True or False?

Answer 5

False.

Quinolones are bacteriostatic at low concentrations and bactericidal at high enough concentrations.

Question 6

Classify quinolones.

Answer 6

i. First generation:- Basic activity and minimal serum level.
ii. Second generation:- Increased gram negative and systemic activity.
iii. Third generation:- Expanded gram positive activity.
iv. Fourth generation:- Expanded gram positive activity with some activity against anaerobes.

Question 7

Give 3 examples of 1st generation quinolones.

Answer 7

i. Nalidixic acid
ii. Oxolinic acid
iii. Cinoxacin

Question 8

Give 3 examples of 2nd generation quinolones.

Answer 8

i. Ciprofloxacin
ii. Lomefloxacin
iii. Ofloxacin
iv. Norfloxacin
v. Enoxacin

CLONE

Question 9

Give 3 examples of 3rd generation quinolones.

Answer 9

i. Levofloxacin
iii. Moxifloxacin
iv. Sparfloxacin

LMS

Question 10

Give an examples of 4th generation quinolones.

Answer 10

i. Trovafloxacin

Question 11

Mention 7 adverse effects of quinolones.

Answer 11

1. Erosion of cartilage in the young
2. GIT disturbance
3. Cardiotoxicity
4. Hepatotoxicity
5. Headache
6. Dizziness
7. Insomnia
8. Disabling effect of fluoroquinolones on joints, tendons, muscles, nerves

Question 12

Highlight the interactions of quinolones.

Answer 12

• They form stable complexes with metal ions hence should not be co-administered with antacids or other drugs containing Al, Mg, Ca, Fe and Zinc.
• Some quinolones inhibit metabolic clearance of theophylline and caffeine, causing an increase in their concentration to toxic levels.

Question 13

Provide the chemical structures and IUPAC names for the following:
i. Nalidixic acid
ii. Basic quinolone structure
iii. Ciprofloxacin
iv. Perfloxacin
v. Norfloxacin
vi. Ofloxacin
vii. Trovafloxacin

Answer 13

………

Note: Basic quinolone structure as well as the other quinolones are 3- quinoline carboxylic acids (note the absence of N in the left conjoined ring), except Trovafloxacin, which just like Nalidixic acid, is a 1, 8- naphthyridine 3- carboxylic acid

Question 14

Highlight the SAR of quinolones.

Answer 14

1. 4-keto and 3-carboxyl group are essential for antibacterial activity.
2. Ring condensation at 1 - 8 position increases activity
3. 6-fluoro group increases potency
4. 7-piperazinyl group increases antibacterial activity.
5. 1-cyclopropyl group increases antibacterial activity

Question 15

What are macrolides?

Answer 15

They are macrocyclic lactones with a primary ring that contains 12-20 carbon atoms.

Question 16

Mention 3 macrolides.

Answer 16

i. Carbomycin
ii. Erythromycin
iii. Oleandomycin

CEO

Question 17

Mention 3 semi-synthetic derivatives of macrolides.

Answer 17

i. Azithromycin
ii. Roxithromycin
iii. Clarithromycin

ARC

*Derivatives are better tolerated and have broader spectrum of activity

Question 18

What is the activity spectrum of macrolides?

Answer 18

They are mostly active against gram positive bacteria and have limited activity against gram negative bacteria.

Question 19

What is the mechanism of action of macrolides?

Answer 19

They bind to the bacterial 50s ribosomal subunit and inhibit the translocation step in protein synthesis.

Question 20

What are the uses of macrolides?

Answer 20

Treatment of respiratory and soft tissue infections

Question 21

Why is erythromycin administered as enteric coated preparations of the free base or as acid-resistant salts and esters such as estolate and succinates?

Answer 21

Because erythromycin is destroyed by gastric acid.

Question 22

Mention 5 side effects of macrolides.

Answer 22

i. nausea
ii. vomiting
iii. diarrhea
iv. hypersensitivity
v. hepatic dysfunction vi. abdominal pain.

Question 23

Highlight the interactions of macrolides.

Answer 23

Macrolides, except azithromycin, inhibit Cytochrome P450, impairing the metabolism of CCBs leading to hypotension in hypertensive patients on therapeutic doses.

Question 24

Provide the structures for Erythromycin A, B and C and Clarithromycin.

Answer 24

…………

Tip: Start by drawing a 14-membered lactone ring, beginning with the ketone group on 1. Remember O is the last member at 14. It should look like 3 benzene rings fused together, without the lines of fusion.

Substitute:
- an ethyl on 13 of the ring.
- CH3 on 2, 4, 6, 8, 10
- OH on 6, 11, 12
- a keto group on 9
- an oxo on 3 and 5 (for glycosidic bonding)

Question 25

Mention 3 essential structural features of macrolides

Answer 25

i. Macrocyclic lactone ring
ii. Sugars or amino sugars
iii. Diethylamine moeity on the sugar